PROJECT SUMMARY/ ABSTRACT This is an application for a K23 award for Dr. Carolyn Hendrickson, a pulmonary and critical care physician at the University of California, San Francisco. Dr. Hendrickson is establishing herself as a young investigator in patient-oriented research of acute respiratory distress syndrome (ARDS), with a focus on the biologic mechanisms of ARDS after traumatic brain injury (TBI). This K23 award will provide Dr. Hendrickson with the support necessary to accomplish the following goals: (1) to become an expert clinical and translational researcher in ARDS after traumatic injury; (2) to study the biologic mechanisms of ARDS after TBI involving platelet biology, endothelial activation, and lung injury induced by mechanical ventilation; (3) to implement advanced analyses of complex observational data, including machine learning; (4) to develop an independent translational research career. Dr. Hendrickson's plan to achieve these goals is supported by a multidisciplinary mentoring team of experts. Her primary mentor, Dr. Michael Matthay, has extensive experience in translational ARDS research and in the career development of early stage investigators. Dr. Hendrickson will work with four co-mentors: Dr. Mitchell Cohen, a translational researcher studying coagulation after trauma, Dr. Alan Hubbard, a biostatistician specializing in causal inference, Dr. Geoffrey Manley, a neurosurgeon and leading investigator in TBI research, and Dr. Mark Looney, an expert platelet biology and lung injury. The development of ARDS after TBI is common and is associated with worse neurological outcomes. The biologic mechanisms driving ARDS after TBI are poorly understood. The central hypothesis of this proposal is that the risk of ARDS after TBI is mediated through activated vascular endothelium and platelets as well as non-protective mechanical ventilation strategies that use large tidal volumes. Dr. Hendrickson will investigate these causal pathways utilizing previously collected data and plasma from an ongoing observational cohort study. In this same cohort she will prospectively collect biospecimens, detailed mechanical ventilation data, and lung ultrasound images. This proposal represents an innovative approach to studying ARDS after TBI using carefully adjudicated exposures and outcomes. Dr. Hendrickson will test whether plasma biomarkers of endothelial activation, vascular permeability, and inflammation (Aim 1) and platelet function, activation, and aggregation (Aim 2) are associated with ARDS after TBI. She will collect lung ultrasound images and frequent mechanical ventilation data including tidal volumes and plateau pressures. She will test whether early exposure to non-protective mechanical ventilation is associated with ARDS after TBI (Aim 3). Addressing this gap in knowledge may lead to interventions that prevent ARDS and improve outcomes in this patient population. The research and training outlined in this proposal will form the basis for an R01-level proposal designed to study interventions to prevent and treat ARDS after traumatic injury.